1. Field of Invention
The present invention relates to a 5-nitrobenzoate derivative and its use as an anti-metastatic agent for the treatment of tumors, particularly tumors that metastasize, via the inhibition of tumor cell-induced platelet aggregation (TCIPA).
2. Description of Related Arts
Tumor cells can stimulate platelet activation and form the aggregation complex with platelets in the vascular circulation system. This interaction is termed as tumor cell-induced platelet aggregation (TCIPA). The ability of tumor cells to induce platelet aggregation has been proven to highly correlate with the metastatic capability of malignant tumor. At present, it is known that there are many factors and mechanisms involved in TCIPA. For instance, tumor cells activate coagulation cascade via thrombin generation and induce platelet aggregation. Besides, adenosine diphosphate (ADP) release is involved in MCF-7 tumor cells-induced platelet aggregation that is relevant to the expression of platelet surface P2Y12 receptor (Alonso-Escolano et al., Br. J. Pharmacol. 141: 241-252, 2004). Other factors including (1) proteinases: cathepsin B and matrix metalloprotease (MMPs), (2) thromboxane A2 and prostacyclin, (3) nitric oxide (NO), (4) platelet surface proteins (e.g. GPIb-IX-V, GPIIb/IIIa and P-selectin, etc.) and so on are involved in TCIPA (Jurasz et al., Br. J. Pharmacol. 143: 819-826, 2004). Based on these results, the detail mechanism of TCIPA seems to very complicated and still be obscured. Nevertheless, these results highlight TCIPA as a target for development of cancer therapeutic strategies in translational medicine.
As so far, various approaches and anti-platelet agents have been reported to inhibit TCIPA that potentially can be used as the strategies for treatment of tumor metastasis. For example, the anti-platelet/coagulation molecule heparin can reduce the cancer-associated thromboembolism risk. In clinic, low molecular weight heparin (LMWH) is administrated to cancer patients to inhibit factor Xa and thrombin to block platelet aggregation, despite that LMWH is not tumor-specific and LMWH overdose usually increases the bleeding risk of cancer patients (Borsig, Progress in Molecular Biology and Translational Science. 93: 335-349, 2010; Lee, et al., N. Engl. J. Med. 349: 146-153, 2003). A common salicylate acid drug, aspirin, inhibits cyclooxygenase (COX) and subsequently blocks thromboxane A2 (TXA2) generation and platelet aggregation. Nevertheless, high dose aspirin does not show specificity and does not have effects on cancer metastasis and patient protection in clinics (Jurasz et al., Br. J. Pharmacol. 143: 819-826, 2004). Recently, utilizing antibody to obstruct the interaction between platelets and tumor cells serves as a promising approach to block metastasis. For example, anti-aggrus/podoplanin antibody has been used to inhibit the interaction of TCIPA between the transmembrane protein (“podoplanin”) of cancer cell and C-type lectin-like receptor 2 (CLEC-2) of platelet. Antibody therapy is usually expensive and patients might suffer from the risk of autoantibody generation (Nakazawa et al., Cancer Sci. 102: 2051-2057, 2011). On the whole, the problems in the prior art lie in that the functions of platelet aggregation are still influenced such that tumor cells cannot be specifically inhibited and TCIPA is not efficiently inhibited.
In view of the above, there exists in the relevant art a need of an improved medicament that may address the above mentioned difficulty encountered in the prior art.